Cancer is controlled by multiple dominant, positive regulators of the transformed state (oncogenes) as well as multiple recessive, negative regulators (tumour suppressor genes). In the oncogene family over one hundred different regulators have been characterised to date. In contrast, fewer than a dozen tumour suppressor genes have been characterised, however, this number is expected to increase beyond fifty.
The presence of so many genes involved in growth control mechanisms in cells underpins the complexity of the development of cancer and the complex processes that a cell has to maintain the integrity of normal tissue. This complexity is manifest in another way. So far, no single gene has been shown to participate in the development of all, or even the majority of human cancers. The most common oncogenic mutations are in the H-ras gene, found in 10-15% of all solid tumours. The most frequently mutated tumour suppressor genes are the p53 gene, homozygously deleted in roughly 50% of all tumors, and CDKN2, which was homozygously deleted in 46% of tumour cell lines examined.
The minor suppressor genes which have been cloned and characterized influence susceptibility to: 1) Retinoblastoma (RB1); 2) Wilms' tumour (WT1); 3) Li-Fraumeni (TP53); 4) Familial adenomatous polyposis (APC); 5) Neurofibromatosis type 1 (NF1); 6) Neurofibromatosis type 2 (NF2); 7) von Hippel-Lindau syndrome (VHL); 8) Multiple endocrine neoplasia type 2A (MEN2A); and 9) Melanoma (CDKN2).
Some of the tumour suppressor loci that have been mapped genetically but not yet isolated include genes for: Multiple endocrine neoplasia type 1 (MEN1); Lynch cancer family syndrome 2 (LCFS2); Neuroblastoma (NB); Beckwith-Wiedemann syndrome (BWS); Renal cell carcinoma (RCC); Tuberous sclerosis 1 (TSC1); and Tuberous sclerosis 2 (TSC2). The tumour suppressor genes that have been characterized to date encode products with similarities to a variety of protein types, including DNA binding proteins (WT1), ancillary transcription regulators (RB1), GTPase activating proteins or GAPs (NF1), cytoskeletal components (NF2), membrane bound receptor kinases (MEN2A), cell cycle regulators (CDKN2) and others with no obvious similarity to known proteins (APC and VHL).
In many cases, the tumour suppressor gene originally identified through genetic studies has been shown to be lost or mutated in some sporadic tumours. This result suggests that regions of chromosomal aberration may signify the position of important tumour suppressor genes involved both in genetic predisposition to cancer and in sporadic cancer.
One of the hallmarks of several tumour suppressor genes characterized to date is that they are deleted at high frequency in certain tumour types. The deletions often involve loss of a single allele, a so-called loss of heterozygosity, but may also involve homozygous deletion of both alleles. For loss of heterozygosity, the remaining allele is presumed to be nonfunctional, either because of a pre-existing inherited mutation, or because of a secondary sporadic mutation.
The present invention provides a novel tumour suppressor gene that has not previously been characterised.
General
Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variation and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in the specification, individually or collectively, and any and all combinations or any two or more of the steps or features.
The present invention is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally equivalent products, compositions and methods are clearly within the scope of the invention as described herein.
All references cited, including patents or patent applications are hereby incorporated by reference. No admission is made that any of the references constitute prior art.
As used herein the term “derived from” shall be taken to indicate that a specific integer may be obtained from a particular source albeit not necessarily directly from that source.
Throughout this specification, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.
Other definitions for selected terms used herein may be found within the detailed description of the invention and apply throughout.